Cushing's Syndrome - Detailed Pointwise Notes

Note: Davidson's Principles and Practice of Medicine is not available in this textbook library. The following is sourced exclusively from Harrison's 22e, the most current edition available.

1. DEFINITION

• Cushing's syndrome is the constellation of clinical features resulting from chronic exposure to excess glucocorticoids of any cause.
• "Cushing's disease" refers specifically to the subset caused by a pituitary corticotrope adenoma (as originally described by Harvey Cushing in 1912).

2. ETIOLOGY AND CLASSIFICATION

A. ACTH-Dependent (90% of endogenous cases)

B. ACTH-Independent (10% of endogenous cases)

C. Iatrogenic (Exogenous) - Most Common Overall

• By far the most common cause; approximately 1% of the population uses chronic glucocorticoid treatments.
• Endogenous Cushing's is a rare disease: incidence of 1.8-3.2 per million per year.

3. PATHOGENESIS AND MOLECULAR BASIS

Cushing's Disease (Pituitary)

• In at least 90% of Cushing's disease, ACTH excess is caused by a corticotrope pituitary microadenoma, often only a few mm in diameter.
• Macroadenomas (>1 cm) occur in only 5-10% and may be invasive, affecting the optic chiasm and cavernous sinuses.
• Most common somatic mutation: USP8 gene (deubiquitinating enzyme) - found in 11-62% of corticotrope adenomas. This leads to constitutive activation of EGF signaling and upregulated expression of the ACTH precursor POMC.
• Less frequent mutations: NR3C1 (glucocorticoid receptor), BRAF, USP48, TP53.
• Can rarely occur in the context of MEN 1, MEN 4, Carney complex, DICER1 syndrome, Lynch syndrome.

Ectopic ACTH Syndrome

• Predominantly caused by occult carcinoid tumors, most often in the lung, also thymus or pancreas.
• Advanced small-cell lung cancer can also produce ectopic ACTH.
• Rare sources: medullary thyroid carcinoma, pheochromocytoma (co-secreting catecholamines + ACTH).

Adrenal Causes (ACTH-Independent)

• Adrenocortical adenomas: activating somatic mutations in PRKACA (PKA catalytic subunit) in ~40%.
• Less frequently: inactivating defects of PRKAR1A or GNAS.
• PPNAD (Primary Pigmented Nodular Adrenal Disease): germline mutations in PRKAR1A; part of Carney's complex (autosomal dominant) - associated with cardiac/cutaneous myxomas, hyperlentiginosis, Sertoli cell tumors, ovarian tumors.
• McCune-Albright syndrome: GNAS activating mutations; associated with polyostotic fibrous dysplasia, café-au-lait spots, precocious puberty.

Mechanism of Glucocorticoid Excess Effects

• Excess glucocorticoids cause upregulation of gluconeogenesis, lipolysis, and protein catabolism.
• Excess cortisol overcomes 11β-HSD2 in the kidney (which normally inactivates cortisol to cortisone), exerting mineralocorticoid effects (hypertension, hypokalemia, edema).
• Interferes with central regulatory systems → suppression of gonadotropins (hypogonadism, amenorrhea) and hypothalamic-pituitary-thyroid axis (↓TSH).

4. CLINICAL FEATURES

Body Fat / Habitus

• Central/truncal obesity (80%) - centripetal fat redistribution
• Moon face (rounded facies) (75%) - plethoric
• Buffalo hump - dorsocervical fat pad
• Weight gain >115% ideal body weight (80%)
• Truncal obesity (50%)

Skin (very discriminatory features)

• Thin, brittle skin (80%)
• Purple/violaceous striae - broad, >1 cm (65%) - highly specific
• Easy bruising (45%)
• Facial plethora (60%)
• Acne (45%)
• Hirsutism (65%) - from excess androgens
• Hyperpigmentation (20%) - seen especially in ectopic ACTH syndrome (due to elevated ACTH/MSH)

Musculoskeletal

• Proximal muscle weakness / myopathy (50%) - difficulty climbing stairs, getting up from a chair; prominent atrophy of gluteal and upper leg muscles
• Osteoporosis / osteopenia (40%) - vertebral fractures; early osteoporosis in children and young women
• Decreased linear growth in children

Cardiovascular / Metabolic

• Hypertension (75%)
• Hypokalemic alkalosis (15%) - more prominent in ectopic ACTH syndrome (seen in ~70% of ectopic ACTH vs <10% of pituitary Cushing's)
• Abnormal glucose tolerance (55%), Diabetes mellitus (15%)
• Dyslipidemia
• Edema of lower extremities (30%)
• Atherosclerosis - primary cause of death is cardiovascular disease
• Hypercoagulable state → increased risk of DVT and pulmonary embolism

Reproductive System

• Menstrual disorders/amenorrhea in women (60%) - due to cortisol-mediated inhibition of gonadotropin release
• Decreased libido
• Impotence in men (55%)

Neuropsychiatric / CNS

• Mental changes (45%): irritability, emotional lability, depression (most common), insomnia, cognitive defects
• Acute paranoid or depressive psychosis in severe cases
• Risk of suicide is increased

Hematological / Immune

• Leukocytosis, lymphopenia, eosinopenia
• Immune suppression: delayed hypersensitivity, increased infection propensity

Features Suggesting Ectopic ACTH Specifically

• Rapid onset of features (vs slow onset in pituitary Cushing's)
• Hyperpigmentation (excess ACTH/MSH)
• Severe myopathy
• Hypokalemia (K <3.3 mmol/L in ~70%)
• Severe hypertension, hypokalemic alkalosis, glucose intolerance, edema - more pronounced

5. DIAGNOSIS

Step 1: Confirm Hypercortisolism (Screening Tests)

1. 24-hour Urinary Free Cortisol (UFC) - precise and cost-effective screening; should be elevated in ≥3 separate collections
2. Overnight 1-mg Dexamethasone Suppression Test (DST) - failure to suppress morning cortisol (>1.8 µg/dL) suggests Cushing's
3. Late-night salivary cortisol or midnight serum cortisol - elevated levels indicate loss of normal diurnal rhythm (physiologic nadir is at night)

• Incomplete 24-h urine collection
• Rapid dexamethasone inactivation: CYP3A4-inducing drugs (antiepileptics, rifampicin)
• Oral contraceptives (↑CBG → elevated total cortisol) - retest 4-6 weeks after stopping
• Pseudo-Cushing states: alcohol-related hypercortisolism, major depression, morbid obesity, cyclic Cushing's syndrome

Step 2: Determine ACTH-Dependence

• Basal plasma ACTH:
  • Suppressed ACTH (< ~5-10 pg/mL) → ACTH-independent (adrenal cause)
  • Normal or elevated ACTH → ACTH-dependent (pituitary or ectopic)
  • ACTH levels in ectopic syndrome are about eightfold higher than in pituitary disease; but there is extensive overlap, so ACTH alone cannot reliably distinguish the two

Step 3: Differential Diagnosis of ACTH-Dependent Cushing's

• Performed at baseline and 2, 5, 10 min after IV CRH (1 µg/kg).
• Central:peripheral ACTH ratio >2 basally and >3 post-CRH confirm pituitary ACTH-secreting adenoma.
• Sensitivity >95%, very rare false-positives.
• Contraindicated in hypertension, cerebrovascular disease, or if pituitary adenoma is well-visualized on MRI.
• Neurovascular complications in ~0.05%.

Step 4: Imaging

• Imaging is only performed after biochemical localization.
• MRI pituitary with gadolinium: only ~50% of ACTH-secreting microadenomas are visible (most are <5 mm).
• High prevalence of incidental pituitary microadenomas complicates interpretation.
• Adrenal CT/MRI: for ACTH-independent disease
  • Adenoma appears as unilateral mass
  • Bilateral adrenal hyperplasia in ACTH-dependent disease
  • Bilateral macronodular hyperplasia for that rare subtype
• Ectopic ACTH: CT chest/abdomen/pelvis to locate occult carcinoid tumor

6. TREATMENT

A. ACTH-Independent (Adrenal) Disease

• Surgical removal of the adrenal tumor or nodular hyperplasia.
• Benign tumors: minimally invasive laparoscopic approach.
• Suspected malignancy: open approach preferred.

B. Cushing's Disease (Pituitary ACTH-Adenoma)

• Selective transsphenoidal resection (endoscopic approach) is treatment of choice.
• Remission rates:
  • Microadenomas: ~80%
  • Macroadenomas: <50%
  • Poor when tumor not visible on MRI
• Post-operatively: symptomatic ACTH deficiency lasting up to 12 months → low-dose hydrocortisone replacement required.
• Biochemical recurrence in ~5% of initially successful cases.
• Prophylactic post-operative thromboembolic management warranted.

• Repeat surgery - especially if pituitary source well-documented
• Pituitary irradiation (fractionated radiotherapy or stereotactic radiosurgery) - cures only ~15% of adults; effects slow, used with steroidogenic inhibitors
• Medical therapy (see below)
• Bilateral adrenalectomy - immediate cure but requires life-long corticosteroid replacement; risk of Nelson's syndrome (expansion of ACTH-secreting tumor post-adrenalectomy)

C. Medical Therapy - Steroidogenesis Inhibitors / Other Agents

D. Post-Cure HPA Axis Recovery

• Requires hydrocortisone replacement started at time of surgery, slowly tapered.
• Recovery rates and median time:
  • Ectopic ACTH syndrome: best recovery (80%; median 7 months)
  • Cushing's disease (pituitary): intermediate (60%; median 17 months)
  • Adrenal Cushing's: lowest recovery (40%; median 30 months)

7. COMPLICATIONS AND PROGNOSIS

• Overt Cushing's is associated with poor prognosis if untreated.
• Primary cause of death: cardiovascular disease.
• Other serious risks: DVT/pulmonary embolism (hypercoagulable state), life-threatening infections, risk of suicide.
• Even after cure: persistently impaired quality of life, increased risk of cardiovascular disease and vertebral fractures depending on duration and degree of cortisol excess.

8. PSEUDO-CUSHING STATES (Differential Diagnosis)

• Alcohol-related non-neoplastic hypercortisolism
• Major depression
• Morbid obesity
• Cyclic Cushing's syndrome (cyclically active, may require repeated testing)

Note on Davidson's: The library does not include Davidson's Principles and Practice of Medicine. The content above is comprehensive and current from Harrison's 22e (2025), which is the primary reference for USMLE/postgraduate examinations. If you need Davidson's-specific content (e.g., for UK/Indian PG exams), please let me know.